Location of the River Euphrates in the Late Miocene; dating of terrace gravel at Shireen, Syria

International audienceWe report gravel of the River Euphrates, capped by basalt that is Ar-Ar dated to ~9 Ma, at Shireen in northern Syria. This gravel, preserved by the erosion-resistant basalt, allows us for the first time to reconstruct the history of this major river during the Late Miocene. In response to progressive regional surface uplift, the Euphrates extended SE by ~800 km between the early Middle Miocene, when the coast was near Kahramanmara? in southern Turkey, and the Pliocene, when it lay in western Iraq, east of the Arabian Platform uplands

Assignment of the Human and Mouse Prion Protein Genes to Homologous Chromosomes

Purified preparations of scrapie prions contain one major macromolecule, designated prion protein (PrP). Genes encoding PrP are found in normal animals and humans but not within the infectious particles. The PrP gene was assigned to human chromosome 20 and the corresponding mouse chromosome 2 using somatic cell hybrids. In situ hybridization studies mapped the human PrP gene to band 20p12→pter. Our results should lead to studies of genetic loci syntenic with the PrP gene, which may play a role in the pathogenesis of prion diseases or other degenerative neurologic disorders

Early Cenozoic denudation of central west Britain in response to transient and permanent uplift above a mantle plume

Upwelling mantle plumes beneath continental crust are predicted to produce difficult to quantify, modest uplift and denudation. The contribution of permanent and transient components to the uplift is also difficult to distinguish. A pulse of denudation in Britain in the Early Paleogene has been linked, although with some controversy, with the arrival of the proto-Iceland mantle plume. In this contribution we show that combining apatite and zircon (U-Th-Sm)/He and apatite fission track analyses from central west Britain with numerical modeling clearly identifies a pulse of early Cenozoic denudation. The data indicate that rock uplift and denudation were centered on the northern East Irish Sea Basin and 1.0–2.4 km of rocks were removed during the latest Cretaceous-early Paleogene. Uplift and erosion appears to have started a few million years before the earliest magmatism in the region. The regional denudation pattern mirrors the distribution of low-density magmatic rocks that has been imaged in the deep crust. However, the injection of the underplating melt is not enough to account for the total denudation. An additional regional uplift of at least 300 m is required, which is consistent with a transient thermal effect from the hot mantle plume. The rapid exhumation event ceased by ~40 Ma and the data do not require significant Neogene exhumation

Assessing health and well-being among older people in rural South Africa

Background: The population in developing countries is ageing, which is likely to increase the burden of noncommunicable diseases and disability. Objective: To describe factors associated with self-reported health, disability and quality of life (QoL) of older people in the rural northeast of South Africa. Design: Cross-sectional survey of 6,206 individuals aged 50 and over. We used multivariate analysis to examine relationships between demographic variables and measures of self-reported health (Health Status), functional ability (WHODASi) and quality of life (WHOQoL). Results: About 4,085 of 6,206 people eligible (65.8%) completed the interview. Women (Odds Ratio (OR) 1.30, 95% CI 1.09, 1.55), older age (OR2.59, 95% CI 1.97, 3.40), lower education (OR1.62, 95% CI 1.31,2.00), single status (OR1.18, 95% CI 1.01, 1.37) and not working at present (OR1.29, 95% CI 1.06, 1.59) were associated with a low health status. Women were also more likely to report a higher level of disability (OR1.38, 95% CI 1.14, 1.66), as were older people (OR2.92, 95% CI 2.25, 3.78), those with no education (OR1.57, 95% CI 1.26, 1.97), with single status (OR1.25, 95% CI 1.06, 1.46) and not working at present (OR1.33, 95% CI 1.06, 1.66). Older age (OR1.35, 95% CI 1.06, 1.74), no education (OR1.39, 95% CI 1.11, 1.73), single status (OR1.28, 95% CI 1.10, 1.49), a low household asset score (OR1.52, 95% CI 1.19, 1.94) and not working at present (OR1.32; 95% CI 1.07, 1.64) were all associated with lower quality of life. Conclusions: This study presents the first population-based data from South Africa on health status, functional ability and quality of life among older people. Health and social services will need to be restructured to provide effective care for older people living in rural South Africa with impaired functionality and other health problems

Understanding communication pathways to foster community engagement for health improvement in North West Pakistan

Background: This paper describes the community engagement process undertaken to ascertain the focus, development and implementation of an intervention to improve iodised salt consumption in rural communities in North West Pakistan. The Jirga is a traditional informal structure, which gathers men respected within their community and acts in a governing and decision making capacity in the Pukhtoon culture. The Jirga system had a dual purpose for the study; to access men from the community to discuss the importance of iodised salt, and as an engagement process for the intervention. Methods: A number of qualitative data collection activities were undertaken, with Jirga members and their wives, male and female outreach workers and two groups of women, under and over forty years old. The aim of these were to highlight the communication channels and levers of influence on health behaviour, which were multiple and complex and all needed to be taken into consideration in order to ensure successful and locally sensitive community engagement. Results: Communication channels are described within local families and the communities around them. The key influential role of the Jirga is highlighted as linked both to the standing of its members and the community cohesion ethos that it embodies. Engaging Jirga members in discussions about iodised salt was key in designing an intervention that would activate the most influential levers to decision making in the community. Gendered decision making-processes within the household have been highlighted as restricting women’s autonomy. Whilst in one respect our data confirm this, a more complex hierarchy of decisional power has been highlighted, whereby the concept of ‘wisdom’, an amalgamation of age, experience and education, presents important possibilities. Community members with the least autonomy are the youngest uneducated females, who rely on a web of socially and culturally determined ways to influence decision-making. Conclusions: The major lines of communication and influence in the local community described are placed within the wider literature on community engagement in health improvement. The process of maximisation of local cultural knowledge as part of a community engagement effort is one that has application well beyond the particular setting of this study

Phenotypic heterogeneity and genetic modification of P102L inherited prion disease in an international series

The largest kindred with inherited prion disease P102L, historically Gerstmann-Sträussler-Scheinker syndrome, originates from central England, with émigrés now resident in various parts of the English-speaking world. We have collected data from 84 patients in the large UK kindred and numerous small unrelated pedigrees to investigate phenotypic heterogeneity and modifying factors. This collection represents by far the largest series of P102L patients so far reported. Microsatellite and genealogical analyses of eight separate European kindreds support multiple distinct mutational events at a cytosine-phosphate diester-guanidine dinucleotide mutation hot spot. All of the smaller P102L kindreds were linked to polymorphic human prion protein gene codon 129M and were not connected by genealogy or microsatellite haplotype background to the large kindred or each other. While many present with classical Gerstmann-Sträussler-Scheinker syndrome, a slowly progressive cerebellar ataxia with later onset cognitive impairment, there is remarkable heterogeneity. A subset of patients present with prominent cognitive and psychiatric features and some have met diagnostic criteria for sporadic Creutzfeldt-Jakob disease. We show that polymorphic human prion protein gene codon 129 modifies age at onset: the earliest eight clinical onsets were all MM homozygotes and overall age at onset was 7 years earlier for MM compared with MV heterozygotes (P = 0.02). Unexpectedly, apolipoprotein E4 carriers have a delayed age of onset by 10 years (P = 0.02). We found a preponderance of female patients compared with males (54 females versus 30 males, P = 0.01), which probably relates to ascertainment bias. However, these modifiers had no impact on a semi-quantitative pathological phenotype in 10 autopsied patients. These data allow an appreciation of the range of clinical phenotype, modern imaging and molecular investigation and should inform genetic counselling of at-risk individuals, with the identification of two genetic modifiers

Climate, people and faunal succession on Java, Indonesia: evidence from Song Gupuh

Song Gupuh, a partially collapsed cave in the Gunung Sewu Limestones of East Java, Indonesia, contains over 16 m of deposits with a faunal sequence spanning some 70 ka. Major changes in the range of animals represented show the impact of climate change and humans. The Terminal Pleistocene and Early Holocene was a period of maximum biodiversity. Human use of Song Gupuh and other cave sites in the region also intensified significantly from ca. 12 ka, together with a new focus on exploitation of small-bodied species (macaque monkeys and molluscs), the first evidence for import of resources from the coast, and use of bone and shell tools. Human activity, especially after the onset of the Neolithic around 2.6 ka, subsequently contributed to a progressive loss of many species from the area, including tapir, elephant, Malayan bear, rhino and tiger, and this extinction process is continuing. We conclude by discussing the biogeographical significance of Song Gupuh in the context of other sites in Java (e.g. Punung, Wajak) and further afield (e.g. Liang Bua)

Acute dosing of latrepirdine (Dimebon), a possible Alzheimer therapeutic, elevates extracellular amyloid-beta levels in vitro and in vivo.

BACKGROUND: Recent reports suggest that latrepirdine (Dimebon, dimebolin), a retired Russian antihistamine, improves cognitive function in aged rodents and in patients with mild to moderate Alzheimer's disease (AD). However, the mechanism(s) underlying this benefit remain elusive. AD is characterized by extracellular accumulation of the amyloid-beta (Abeta) peptide in the brain, and Abeta-lowering drugs are currently among the most popular anti-amyloid agents under development for the treatment of AD. In the current study, we assessed the effect of acute dosing of latrepirdine on levels of extracellular Abeta using in vitro and in vivo experimental systems. RESULTS: We evaluated extracellular levels of Abeta in three experimental systems, under basal conditions and after treatment with latrepirdine. Mouse N2a neuroblastoma cells overexpressing Swedish APP were incubated for 6 hr in the presence of either vehicle or vehicle + latrepirdine (500pM-5 muM). Synaptoneurosomes were isolated from TgCRND8 mutant APP-overexpressing transgenic mice and incubated for 0 to 10 min in the absence or presence of latrepirdine (1 muM or 10 muM). Drug-naïve Tg2576 Swedish mutant APP overexpressing transgenic mice received a single intraperitoneal injection of either vehicle or vehicle + latrepirdine (3.5 mg/kg). Picomolar to nanomolar concentrations of acutely administered latrepirdine increased the extracellular concentration of Abeta in the conditioned media from Swedish mutant APP-overexpressing N2a cells by up to 64% (p = 0.01), while a clinically relevant acute dose of latrepirdine administered i.p. led to an increase in the interstitial fluid of freely moving APP transgenic mice by up to 40% (p = 0.01). Reconstitution of membrane protein trafficking and processing is frequently inefficient, and, consistent with this interpretation, latrepirdine treatment of isolated TgCRND8 synaptoneurosomes involved higher concentrations of drug (1-10 muM) and led to more modest increases in extracellular Abeta(x-42 )levels (+10%; p = 0.001); of note, however, was the observation that extracellular Abeta(x-40 )levels did not change. CONCLUSIONS: Here, we report the surprising association of acute latrepirdine dosing with elevated levels of extracellular Abeta as measured in three independent neuron-related or neuron-derived systems, including the hippocampus of freely moving Tg2576 mice. Given the reported association of chronic latrepirdine treatment with improvement in cognitive function, the effects of chronic latrepirdine treatment on extracellular Abeta levels must now be determined.RIGHTS : This article is licensed under the BioMed Central licence at http://www.biomedcentral.com/about/license which is similar to the 'Creative Commons Attribution Licence'. In brief you may : copy, distribute, and display the work; make derivative works; or make commercial use of the work - under the following conditions: the original author must be given credit; for any reuse or distribution, it must be made clear to others what the license terms of this work are